Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center Highlights from the San Antonio Breast Cancer Symposium: Triple-Negative Breast Cancer

Key SABCS Abstracts on Triple Negative Breast Cancer  S5-01. CALGB Addition of carboplatin to neoadjuvant weekly paclitaxel – impact on pCR  S1-06. GeparSixto: Impact of Carboplatin and Tumor infiltrating lymphocytes (TILs)  S1-01. TILs in TNBC: ECOG 2197 and 1199  S5-02. Veliparib/carboplatin plus standard neoadjuvant therapy in TNBC: Results from the I-SPY 2 TRIAL  P BMN 673 in BRCA-mutation-related breast cancer  S6-01. JAK2 in Residual TNBC  S4-03. Sequencing of TNBC metastases – novel genes of specific ontogeny and association with outcome

CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC Sikov WM, et al. SABCS 2013, Abstract S5-01 Stage II-III TNBC (N = 443) Paclitax. 80 mg/m 2 qw x 12 Carbo AUC 6 q3w x 4 Paclitax. 80 mg/m 2 qw x 12 Bevaciz. 10 mg/kg q2w x 9 Paclitax. 80 mg/m 2 qw x 12 Carbo AUC 6 q3w x 4 Bevaciz. 10 mg/kg q2w x 9 dd AC X 4 Surgery + Radiation as needed

CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC Sikov WM, et al. SABCS 2013, Abstract S5-01

CALGB 40603: Pathologic CR (ypT0/is N0) pCR % No Carbo (N = 212) Carbo (N = 221) All (N = 433) No Bev (N = 218) OR = 1.36 p = Bev (N = 215) All (N = 433)4154 OR = 1.71; p = Carbo/Bev interaction p =.43 Sikov WM, et al. SABCS 2013, Abstract S5-01

*1 death due to uncontrolled hypertension. CALGB – Serious Adverse Events Chemo Chemo + Bev Chemo + Carbo Chemo + Carbo + Bev N Evaluable Total FN during AC Nausea/vomiting/ dehydration 1556 Bleeding0205 DVT or PE1614 Infection (normal ANC) GI perforation0101

CALGB 40603: Take Home Points Carboplatin increases pCR rate Bevacizumab show trend toward better pCR rate No interaction between bevacizumab and carboplatin for efficacy Bev leads to more Grade III HTN, febrile neutropenia, bleeding, thrombus, surgical complications Carbo leads to more Gr III/IV neutropenia, thrombocytopenia and attenuates amount of paclitaxel delivered Long-term impact on DFS, OS not known

GeparSixto: Addition of Neo Adj Carboplatin Von Minckwitz G, et al ASCO 2013, Abstract # 1004

GeparSixto: Carboplatin Impact on pCR Von Minckwitz G, et al ASCO 2013, Abstract # 1004

Carboplatin Impact on pCR: HER+ vs. TNBC Von Minckwitz G, et al ASCO 2013, Abstract # 1004

Incremental Improvements in TNBC pCR Von Minckwitz G, et al ASCO 2013, Abstract # Bevacizumab + Platinum

pCR Rates: Based on Tumor-Infiltrating Lymphocytes (TILs) Denkert C, et al. SABCS 2013, Abstract S1-06 P<0.005 P=0.09 P<0.005

GeparSixto: Impact of TILs for Carboplatin Neoadjuvant Tx for TN and HER2+ Early Breast Cancer Denkert C, et al. SABCS 2013, Abstract S1-06 Stromal TILs (per 10%)OR (95% CI)P ValueTest for Interaction All patients  PM1.11 ( )  PM + carboplatin1.35 ( )<.0005 Triple negative  PM1.09 ( )NS0.27  PM + carboplatin1.22 ( ).004 HER2+  PM1.13 ( )NS0.007  PM + carboplatin1.53 ( )<.0005

ECOG 2197 and 1199: Stromal TILs in Adjuvant Therapy for TNBC Adams S, et al. SABCS 2013, Abstract S1-07 DFS Probability DDFS Probability OS Probability P=0.02 Years P=0.05 P=0.03 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 Years

ECOG 2197 and 1199: sTILs in Adjuvant Therapy for TNBC Stromal TILs associated with better prognosis (DFS, DRFI, OS) after standard adjuvant therapy in TNBC (multivariate model) –DFS HR: 0.84 (95% CI: ; P =.005) –DRFI HR: 0.81 (95% CI: ; P =.02) –OS HR: 0.79 (95% CI: ; P =.003) For every 10% incremental gain of stromal TILs: –14% reduction of risk for recurrence/death (P =.02) –18% reduction of risk for distant recurrence (P =.04) –19% reduction of risk for death (P =.01) Adams S, et al. SABCS 2013, Abstract S1-07

Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + New Agent C Eligible for NAC Paclitaxel+ Trastuzumab Paclitaxel + Trastuzumab* + New Agent B Paclitaxel Paclitaxel + New Agent E AC HER 2 (+) HER 2 (–) Randomize Surgery Learn and adapt from each patient as we go along Paclitaxel + New Agent F Paclitaxel + Trastuzumab* + New Agent C Paclitaxel + New Agent D Paclitaxel + New Agent GH Paclitaxel + Trastuzumab* + New Agent F MRI Residual Disease (Pathology) Key I-SPY 2 TRIAL Schema Learn, Drop, Graduate, and Replace Agents Over Time Rugo H, et al. SABCS 2013, Abstract S5-02

Agent Overview DrugClassCompanyStart Date ABT-888 (Veliparib) PARP InhibitorAbbottMarch 2010 Neratinib (HKI-272) Tyrosine Kinase Inhibitor Puma/PfizerMarch 2010 AMG 386Vascular DisruptorAmgenOctober 2011 AMG Metformin IGFR Inhibitor + Metformin AmgenApril 2012 MK2206AKT InhibitorMerckJuly 2012 PertuzumabHER Dimerization Inhibitor Genentech/RocheJune 2013 T-DM1 + Pertuzumab ADC: Trastuzumab + Mertansine Genentech/RocheJune 2013 Rugo H, et al. SABCS 2013, Abstract S5-02

I-SPY 2 Trial Adaptive Design Adaptive randomization –Uses a pre-specified and automated algorithm –Randomization probabilities update as study proceeds »By signature, and based on MRI and pCR results Algorithm triggers the decision to “graduate” when patients are enrolled 85% predicted likelihood of success in a randomized phase 3 neoadjuvant trial –N=300 patients –pCR is the endpoint Rugo H, et al. SABCS 2013, Abstract S5-02

Veliparib/Carboplatin GRADUATES in the Triple Negative Signature SIGNATURE Estimated pCR Rate (95% probability interval) Probability Veliparib + Carbo is Superior to Control Predictive Probability of Success in Phase 3 Veliparib/ Carbo Concurrent Control All HER2- 33% (22-43%) 22% (10-35%) 92%55% HR+/HER2- 14% (4-27%) 19% (6-35%) 28%9% HR-/HER2- 52% (35-69%) 26% (11-40%) 99%90% Rugo H, et al. SABCS 2013, Abstract S5-02

Safety Concurrent Control Veliparib/ Carboplatin N4463 Hematologic, > grade 3 (%) Febrile neutropenia Neutropenia Thrombocytopenia Anemia Gastrointestinal, all < grade 3 (%) Stomatitis Nausea Vomiting Diarrhea9.125 Rugo H, et al. SABCS 2013, Abstract S5-02 Paclitaxel dose reductions in 27%

Response to PARP Inhibitor BMN 673 Phase I Study Mina LA, et al. SABCS 2013, Abstract P /18 patients with TNBC

BMN 673 Update BMN 673 showed single-agent antitumor activity and favorable progression-free survival in BRCA-related advanced breast cancer o 72% clinical benefit rate in in BRCA-related breast cancer o 6% CR, 39% PR, 28% SD ≥ 24 wks Generally well tolerated, with common drug-related toxicities seen in < 30% of patients and include myelosuppression, fatigue, nausea, and alopecia Phase III trial of BMN 673 in combination with chemotherapy in patients with MBC and deleterious germline mutations of BRCA1 or 2 is ongoing and randomized trial compared to physicians choice is planned Mina LA, et al. SABCS 2013, Abstract P

Genomic Analysis of Residual TNBC After Neoadjuvant Therapy Deep Sequencing (Foundation Medicine) for 182 oncogenes in 72 evaluable cases with enough “coverage” JAK2 was novel and not seen in primary cases so far Balko JM, et al. SABCS 2013, Abstract S6-1

JAK2 in TNBC JAK2 is a receptor coupled TK that activates STAT proliferation and differentiation pathway is involved in stem cell maintenance JAK2 mutations and amplification seen in TNBC, with amplification expansion seen upon treatment JAK2 amplification associated with worse survival in TNBC JAK2 inhibitor trials underway in breast cancer Balko JM, et al. SABCS 2013, Abstract S6-1

Exome Sequencing of TNBC Metastases: Pathogenesis and Treatment Targets Germline, Primary, Metastasis Comparisons Blackwell K, et al. SABCS 2013, Abstract S4-03 Primary and Metastatic Mutations N=331 Metastatic-specific N=31 ABCA12, ADAM18 ARGHAP21, BRWD3, CCDC84, DCHS2, DLEC1, DOCK5, DYNCH1, FANCM, GRIN2C, TP53, MTOR, TRPM2, others 4/6 genes with PFS difference involved in macromolecule metabolism